The present disclosure is generally directed to novel compounds having utility as an anesthetic and/or in the treatment of disorders relating to GABA function and activity. More specifically, the present disclosure is directed to cyclopenta[b]phenanthrenes having a substituted tetracyclic structure that are neuroactive and suitable for use as an anesthetic, as well as pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. GABA activates two types of receptors, the inotropic GABAA and the metabotropic GABAB receptor. Activation of the GABAB receptor by GABA causes hyperpolarization and a resultant inhibition of neurotransmitter release. The GABAA receptor subtype regulates neuronal excitability and rapid mood changes, such as anxiety, panic, and stress response. GABAA receptors are chloride ion channels; as a result, activation of the receptor induces increased inward chloride ion flux, resulting in membrane hyperpolarization and neuronal inhibition. Drugs that stimulate GABAA receptors, such as benzodiazepines and barbiturates, have anticonvulsive effects (by reducing neuronal excitability and raising the seizure threshold), as well as anxiolytic and anesthetic effects.
The effect of certain steroids on GABAA receptors has been well-established. As a result, researchers continue to pursue the discovery and synthesis of neuroactive steroids that may act as anesthetics and/or that may serve to provide treatment for disorders related to GABA function. For example, it is now widely accepted that the intravenous anesthetic alphaxalone (Compound A, below) causes general anesthesia in humans because it allosterically increases chloride currents mediated by GABA acting at GABAA receptors in the brain. However, the various structural features that enable this compound to function in the way it does have, to-date, not been fully understood.

In particular, the effect of changing the manner in which the four rings of neurosteroids are connected and the locations of the substituents on them is not completely understood. It was shown for two compounds that moving the B-ring of the steroid cyclopenta[a]phenanthrene ring system to obtain the cyclopenta[b]phenanthrene ring system could yield active compounds as shown in FIG. 1 by creating FIG. 1C from FIG. 1A and by creating FIG. 1D from FIG. 1B (Scaglione, et al., “Neurosteroid Analogues. 14. Alternative Ring System Scaffolds: GABA Modulatory and Anesthetic Actions of Cyclopenta[b]phenanthrenes and Cyclopenta[b]anthracenes,” J. Med. Chem., Vol. 51, Pages 1309-1318 (2008)). The other structural details of additional neuroactive cyclopenta[b]phenanthrenes, however, are unknown and are the subject of this disclosure.
In addition to anesthetic properties, neuroactive cyclopenta[b]phenanthrenes may be used to treat disorders related to GABA function. For example, neuroactive cyclopenta[b]phenanthrenes may be used as sedative-hypnotics, exhibiting benzodiazepine-like actions, inducing reduced sleep latency and increased non-REM sleep with only small changes in slow wave and REM sleep. Further, drugs that enhance GABA responses are often used to treat anxiety in humans. Thus, it might be expected that GABA-potentiating cyclopenta[b]phenanthrenes would exhibit anxiolytic effects. Neuroactive cyclopenta[b]phenanthrenes may also be used to treat depression, given that accumulating evidence suggests that patients with major depression have decreased levels of GABAergic neurosteroids and that certain treatments for depression alter levels of these neurosteroids. Although GABA is not typically thought to play a critical role in the biology of depression, there is evidence that low GABAergic activity may predispose one to mood disorders. Finally, inhibition of NMDA receptors and enhancement of GABAA receptors appear to play important roles in mediating the acute effects of ethanol in the nervous system, while related studies suggest that GABAergic neurosteroids may be involved in some of the pharmacological effects of ethanol and that neuroactive neurosteroids may be useful in treating ethanol withdrawal. Thus, cyclopenta[b]phenanthrenes as analogues of endogenous neurosteroids may be useful for treating these conditions.
In view of the foregoing, it is clear that there are a number of potentially advantageous uses for cyclopenta[b]phenanthrenes. As a result, there is a continuing need for the further synthesis and understanding of new neuroactive cyclopenta[b]phenanthrenes, particularly those having utility as an anesthetic and/or in the treatment of a disorder relating to GABA function and activity.